Limolipin, um repressor transcricional que promove esteatose hepática

• Ano de defesa: 2017
• Autor(a) principal: Fernandes, Gustavo Werpel [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Limolipin; Type 2 deiodinase; Liver; Steatosis; Fatty liver; Iodide peroxidase; DNA-binding proteins; Zfp125 (Limolipin); D2; Fígado; Esteatose; Fígado gorduroso; Iodeto peroxidase; Proteínas de ligação a DNA
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5076022; https://repositorio.unifesp.br/handle/11600/50772

Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO), that encodes the key enzyme that activates thyroid hormone, results in resistance to diet-induced obesity and to liver steatosis in mice. Here we report that this is caused by ~60% reduction in liver zinc finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in AML12 mouse hepatic cell line and liver steatosis in mice by reducing hepatocyte secretion of triglycerides and cholesterol. It acts by repressing 18 genes involved in lipoprotein structure, lipid binding and transport. There is a functional Zfp125-binding element located in the ApoE promoter, also present in 16 other lipid-related genes repressed by Zfp125. Liposome-mediated Zfp125 expression in liver causes steatosis and a ~3-fold increase in circulating VLDL+LDL-cholesterol. While liver-specific knockdown of Zfp125 in control mice causes a “Alb-D2KO-like” metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the metabolic phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis and hypercholesterolemia. These findings explain how a brief perinatal hepatic surge in local thyroid hormone activation affects the Foxo1-Zfp125 pathway and modulate susceptibility to obesity, liver steatosis and hypercholesterolemia later in life.